1. Field of the Invention
The present invention relates to the treatment of complications of diabetes, and particularly to a composition for treating ocular effects of diabetes.
2. Description of the Related Art
In the United States, companion pets number over 62 million dogs and 71 million cats. According to the American Veterinary Medical Association (AVMA), these dogs and cats are living longer due to better nutrition and preventive veterinary care. With over 40% of this population being at least seven years old, more pets are being diagnosed with diabetes mellitus (DM). Although DM occurs at any age, it most frequently is diagnosed in dogs and cats between the ages seven and nine. In 1996, the prevalence of DM in dogs and cats was reported to range between 0.2-1%, i.e., approximately 1 in every 200 dogs and cats was diabetic. A number of complications result from diabetes mellitus, including the formation of cataracts; diabetic retinopathy; corneal lesions, erosion, wound healing complications, epithelial barrier changes, and other corneal pathology; changes in the iris (delay in dilation, fibrous tissue formation, altered vessel permeability, etc.); morphological changes in the ciliary bodies; and other diabetic changes.
Investigations have shown that many of the complications of diabetes result, at least in part, from abnormalities in glucose metabolism through the polyol pathway. Normally the bulk of intracellular glucose is metabolized to provide energy by phosphorylation of glucose, which is catalyzed by hexokinase to form glucose-6-phosphate, which is further metabolized to useful energy by entry into the Krebs cycle. In the diabetic patient, however, insufficient hexokinase is available to metabolize all of the intracellular glucose.
In many tissues of the body, including lens tissue in the eye, an alternative path is available to metabolize glucose. The enzyme aldose reductase (AR) catalyzes the reduction of glucose to sorbitol with hydrogen supplied by NADPH. Sorbitol is then oxidized to fructose by sorbitol dehydrogenase, the hydrogen being accepted by NAD+. However, in the hyperglycemic patient, although sufficient aldose reductase is available to reduce glucose to sorbitol, there is not sufficient sorbitol dehydrogenase to oxidize the sorbitol to fructose.
This leads to an accumulation of sorbitol in the tissues. Sorbitol does not readily diffuse through the tissues and cellular membranes due to its polarity. It is hypothesized that the accumulation of sorbitol produces a hyperosmotic condition, with resulting fluid accumulation in the cells, altering membrane permeability with the development of the pathological conditions noted above. Consequently, considerable attention has focused on the development of aldose reductase inhibitors (ARIs).
With diabetic dogs being prone to develop bilateral cataracts, research into the development thereof has shown that this is related to AR levels in the lens. Research studies have also shown that the oral administration of aldose reductase inhibitors to dogs have been effective in the prevention of cataracts resulting from diabetes, as well as in the treatment of diabetic retinopathy, corneal lesions, and other complications of diabetes mellitus.
Nevertheless, the oral administration of aldose reductase inhibitors has several shortcomings. The dosage of ARIs administered orally is rather high (about four times per day), and must be maintained over a long period of time. Oral administration requires processing by the liver, and may compromise the dog's liver function. Moreover, no studies have yet shown reversal of the formation of cataracts in dogs from the oral administration of aldose reductase inhibitors.
It would be desirable to provide a topical formulation for administering an ARI directly into the dog's eyes. Conventional topical formulations for ARIs are not effective for use on dogs, since such formulations are generally aqueous solutions, and tear flow in dogs is generally greater than in humans, so that it is not possible to maintain therapeutic levels of an ARI, since such formulations are washed out by tear formation. A topical formulation for the administration of an ARI directly into a dog's eyes would be desirable for reduction of dosage and frequency of administration, quicker absorption into the system, and avoiding liver metabolism of the ART.
U.S. Pat. No. 8,158,667, issued Apr. 17, 2012 to Kador et al., describes a topical composition for the treatment of optical complications of diabetes in dogs that comprises a carrier having a specific composition and an aldose reductase inhibitor mixed with the carrier to form an ophthalmic gel. (One of the present inventors, Dr. Milton Wyman, was also a co-inventor in the '667 patent, which is hereby incorporated by reference in its entirety.) A preferred ARI named in the '667 patent is methyl sorbinil, and more particularly preferred, the isomer 2-methyl sorbinil. While the composition of the '667 patent is effective in the treatment of optical complications of diabetes in dogs to the extent described therein, it has been found that the specific carrier described in the '667 patent does not deliver a sufficiently therapeutic amount of the ARI to the dog's eye to exert a preventive, inhibitory, or prophylactic effect to the extent desired. Improvement in the carrier or vehicle of the '667 is therefore desirable.
Thus, a composition for treating ocular effects of diabetes solving the aforementioned problems is desired.